In accordance with the mission of the NIDDK to support research on the most serious diseases affecting public health, the proposed NRSA project is aimed at understanding mechanisms regulating central obesity, which is strongly linked to the development of diabetes, hypertension, and cardiovascular disease. Unlike the classic pathophysiologic model of central obesity (i.e., Cushing's disease), the obese state is not characterized by elevated serum cortisol levels. However, human studies of adipose 11 beta-hydroxysteroid dehydrogenase type 1 (11[unreadable]-HSD1), the enzyme that locally converts the inactive hormone, cortisone, to the active hormone, cortisol, have demonstrated increased mRNA expression and in vitro activity in obese compared with lean subjects. These findings suggest that obesity is associated with increased adipocyte glucocorticoid metabolism, but it remains unclear whether this is a cause or consequence of obesity. To begin addressing this question, the global aim of our proposed studies is to determine the effects of a 5% weight loss on adipose glucocorticoid metabolism in postmenopausal women. Due to the complex, tissue-specific regulation of 11(3-HSD1, we will 1) use a novel microdialysis technique to determine in vivo glucocorticoid metabolism; 2) characterize adipocyte expression of not only 11[unreadable]-HSD1 but also other key regulators of glucocorticoid action including hexose-6-phosphate dehydrogenase (H6PDH) and glucocorticoid receptor alpha (GRa); and 3) compare in vivo activity and in vitro mRNA expression in subcutaneous abdominal and femoral fat, two accessible depots with different metabolic characteristics. We hypothesize that abdominal adipose 11[unreadable]-HSD1 activity will be increased in the weight-reduced, energy balanced state, which would suggest that tissue-specific glucocorticoid metabolism plays a causal role in the development of obesity. Such findings would imply that 11-(3HSD1 inhibitors may be an important pharmacotherapy for weight maintenance and the prevention of weight regain following weight loss. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: The purpose of this research project is to study the effects of weight loss on the metabolism of the stress hormone cortisol in healthy, postmenopausal women. Our goal is to identify possible explanations for the accumulation of fat in the abdominal region. [unreadable] [unreadable] [unreadable] [unreadable]